title: Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates.
abstract: Vancomycin, one of few effective treatments against methicillin-resistant Staphylococcus aureus, is nephrotoxic. The goals of this study were to (1) gain insights into molecular mechanisms of nephrotoxicity at the genomic level, (2) evaluate gene markers of vancomycin-induced kidney injury, and (3) compare gene expression responses after iv and ip administration. Groups of six female BALB/c mice were treated with seven daily iv or ip doses of vancomycin (50, 200, and 400 mg/kg) or saline, and sacrificed on day 8. Clinical chemistry and histopathology demonstrated kidney injury at 400 mg/kg only. Hierarchical clustering analysis revealed that kidney gene expression profiles of all mice treated at 400 mg/kg clustered with those of mice administered 200 mg/kg iv. Transcriptional profiling might thus be more sensitive than current clinical markers for detecting kidney damage, though the profiles can differ with the route of administration. Analysis of transcripts whose expression was changed by at least twofold compared with vehicle saline after high iv and ip doses of vancomycin suggested the possibility of oxidative stress and mitochondrial damage in vancomycin-induced toxicity. In addition, our data showed changes in expression of several transcripts from the complement and inflammatory pathways. Such expression changes were confirmed by relative real-time reverse transcription-polymerase chain reaction. Finally, our results further substantiate the use of gene markers of kidney toxicity such as KIM-1/Havcr1, as indicators of renal injury.
authors.affiliation: Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025-3493, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Dieterich
authors.forename: Angela
authors.initials: A
authors.lastname: Puey
authors.forename: Sylvia
authors.initials: S
authors.lastname: Lin
authors.forename: Sylvia
authors.initials: S
authors.lastname: Lyn
authors.forename: Robert
authors.initials: R
authors.lastname: Swezey
authors.forename: Anna
authors.initials: A
authors.lastname: Furimsky
authors.forename: David
authors.initials: D
authors.lastname: Fairchild
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
authors.forename: Hanna H
authors.initials: HH
authors.lastname: Ng
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism*; D001806:Blood Urea Nitrogen; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014640:Vancomycin / Q000008:administration & dosage / Q000633:toxicity*; D005723:gamma-Glutamyltransferase / Q000032:analysis
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D014640:Vancomycin; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase